tbuckley/cabot-search huggingface dataset:
Abstract LB229: Tinengotinib, a novel fibroblast growth factor receptor (FGFR) inhibitor, is potent against resistance mutations in FGFR1/2/3
Authors: Xiaoyan Qiang, Qi Yu, Jean Fan, Frank Wu, Caixia Sun, Peng Peng
Journal: Cancer Research (2023)

Abstract Dysregulated FGFR alterations (FGFRalt), including gene amplification, hot spot mutations, and gene fusion or rearrangement, have been reported in 7% of solid tumors, functioning as oncogenic drivers independent of tumor types. First generation of FGFR inhibitors, such as erdafitinib and pemigatinib, have already demonstrated promising efficacy on multiple cancers with prespecified FGFRalt. However, certain kinase mutations identified in the clinics, including gatekeeper mutations and some molecular brake mutations, may cause resistance to first generation FGFR inhibitors and remain challenging for current FGFR inhibitor development. Tinengotinib potently inhibited multiple FGFR1/2/3 resistant mutations both in vitro and in vivo. In the biochemical and cellular assays, tinengotinib exhibited potent inhibitory activities against FGFR2 gatekeeper mutation V564F, and molecular brake mutation N549K, which were known to cause resistance to the first generation FGFR inhibitors in cholangiocarcinoma patients with FGFR2 fusion or rearrangement. Binding kinetics was measured using surface plasmon resonance (SPR) on FGFR2, and tinengotinib demonstrated very tight binding to the target. To understand the underlying mechanism, we conducted co-crystallization of tinengotinib and wild type kinase domain of FGFR2. The resulting high-resolution X-ray diffraction structure revealed a very unique binding mode of tinengotinib in the ATP-binding site of FGFR2 comparing to other FGFR inhibitors. In addition, homology model demonstrated similar binding mode of tinengotinib to FGFR 1 and 3. This is consistent with the finding of tinengotinib showing excellent potency to FGFR 1/3 gatekeeper mutations. Tinengotinib is well tolerated in the clinical trials. Retrospective analysis showed early promising efficacy in treating patients with various solid tumors bearing FGFRalt. It provides an opportunity to investigate tinengotinib as a tumor agnostic therapy in patients with prespecified FGFR 1/2/3 alterations (pan-FGFRalt). Citation Format: Xiaoyan Qiang, Qi Yu, Jean Fan, Frank Wu, Caixia Sun, Peng Peng. Tinengotinib, a novel fibroblast growth factor receptor (FGFR) inhibitor, is potent against resistance mutations in FGFR1/2/3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB229.
The Tortoise and the Hare
Authors: Jon O. Lundberg, Tomas Schiffer, Eddie Weitzberg, Filip J. Larsen
Journal: Trends in Endocrinology and Metabolism (2023)

Distance running requires a high absolute oxygen consumption, while for a breath-hold diver the opposite is preferable. We compared physiological exercise parameters and mitochondrial function in a competitive triathlete with those seen in an accomplished breath-hold diver and notice some remarkable differences, possibly explaining why both have become successful.
Abstract LB303: Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer
Authors: Javeria Zaheer, Joycie Shanmugiah, Hyeongi Kim, Jin Su Kim
Journal: Cancer Research (2023)

Abstract The deposition of the extracellular matrix (ECM) is associated with poor prognosis and therapy response in gastric cancer. An elevated extracellular matrix (ECM) and interstitial fluid pressure in gastric cancer limits the targeting of HER2-expressing gastric cancer cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here we used Losartan (LOS), which is an antihypertensive drug, to downregulate ECM and interstitial fluid pressure in gastric cancer mice model. After 40 mg/kg of LOS treatment, a 2-fold higher Alexa-647-TRZ uptake significantly enhanced 64Cu-TRZ uptake by positron emission tomography (PET) imaging, LOS treatment decreased the tumor volume, and enhanced the survival rate. LOS-treated samples showed reduced SERPINE1 mRNA expression compared with the controls, as determined by qRT-PCR. Downregulated mRNA expression of TGFβ-1, and upregulated mRNA expression of MMP-2 in LOS-treated samples were observed. The corresponding protein expression of SERPINE1 was confirmed using western blotting. We also confirmed that silencing of SERPINE1 increased MMP2 activity. We revealed that the enhanced therapeutic effect of 64Cu-TRZ via LOS was due to the downregulation of SERPINE1, which degrades the ECM through MMP2. Our novel combinational therapy of using 64Cu-TRZ with LOS is highly effective for treatment of gastric cancer. Citation Format: Javeria Zaheer, Joycie Shanmugiah, Hyeongi Kim, Jin Su Kim. Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB303.
Abstract LB089: ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors
Authors: Hao-Kang Li, Tai-Sheng Wu, Pei-Ru Leng, Yi-Chiu Kuo, Zih-Fei Cheng, Chia-Yun Lee, Yan-Liang Lin, Sai-Wen Tang, Shih-Chia Hsiao
Journal: Cancer Research (2023)

Abstract Introduction: CAR-αβT therapies have been shown to improve clinical outcomes in hematological malignancies; however, solid tumors still remain as challenges to CAR-αβT therapies due to tumor microenvironment, limited tumor infiltration or antigen escape. Previous research findings indicate γδ2 T cells are involved in tumor surveillance by responding to phosphoantigen overexpressed by most of cancers. The antibody cell conjugation (ACC) technology has the advantage to link cancer-targeting antibodies on cell surface of immune cells without genetic modification. This study applies ACC technology to generate an off-the-shelf EGFR-targeting γδ2 T cell therapy ACE2016, and presents the promising potency of ACE2016 against EGFR-expressing cancer cells. Methods: γδ2 T cells were expanded from healthy donor PBMCs and αβ T cell population were depleted. Both γδ2 T cells and αEGFR were covalently conjugated to selected DNA aptamers that enable DNA hybridization to generate EGFR-targeting γδ2 T cells, ACE2016. The characteristics and antibody conjugation of ACE2016 was evaluated by flow cytometry, and in vitro cytotoxicity and in vivo anti-tumor potency was investigated using luminescence-based cytotoxicity assay and the orthotopical model with EGFR-expressing cancer cells, respectively. Results: ACE2016 showed nearly 100 % of αEGFR antibody conjugation and exhibited EGFR-specific binding activity. These features conferred ACE2016 with enhanced in vitro cytotoxicity against EGFR-expressing cancer cells compared to unconjugated γδ2 T cells, while ACE2016 and γδ2 T cells showed no significant difference of anti-tumor potency against EGFR-negative cancer cells. Further characterization studies demonstrated that co-cultured with target cells significantly activated ACE2016 along with enhanced degranulation and cytokine production without measurable IL-6 secretion. Moreover, ACE2016 suppressed EGFR-expressing breast cancer cells in vivo in the orthotopic xenograft model without weight loss or toxicological observations. Conclusion: ACE2016, an EGFR-targeting γδ2 T cell product, was successfully generated as an effective off-the-shelf treatment for EGFR-expressing solid tumors. This study provides the evidence for the in vitro and in vivo efficacy of ACE2016 against EGFR-expressing cancer cells to support the clinical application against EGFR-expressing tumors. Citation Format: Hao-Kang Li, Tai-Sheng Wu, Pei-Ru Leng, Yi-Chiu Kuo, Zih-Fei Cheng, Chia-Yun Lee, Yan-Liang Lin, Sai-Wen Tang, Shih-Chia Hsiao. ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB089.
Abstract LB222: An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model
Authors: Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Yong Ho Heo, Seongju Jeong, Yu-Yon Kim, In Young Choi
Journal: Cancer Research (2023)

Abstract Kirsten rat sarcoma viral oncogene (KRAS) mutations are present in 26% of non-small cell lung cancer (NSCLC) patients (The Cancer Genome Atlas data). Studies have reported the presence of spatial or intra-tumoral heterogeneity of KRAS mutations. Though resistance to mutant KRAS inhibitors targeting a specific form of major KRAS mutations (e.g, G12C or G12D) is multifaceted, intra-tumoral heterogeneity of KRAS mutation is one of the crucial factors for the intrinsic resistance to the inhibitor. Multi-targeting of different KRAS mutations can prevent resistance due to the heterogeneity of KRAS mutations within a tumor. To achieve this, we incorporated an mRNA-based cancer vaccine containing transcripts for multiple KRAS mutant antigens. Our KRAS cancer vaccine (CV) candidate showed significantly attenuated tumor growth by 37% in the syngeneic KRAS G12C-expressing LL/2 tumor-bearing mice. CV treatment group showed significantly decreased tumor size by 45.4% after biopsy. Moreover, the mice treated with KRAS CV showed spleen enlarged by 42.6% indicating increased immune responses. To confirm, the expansion of T cells in the cancer vaccine-treated group, we collected tumor tissues and analyzed proportions of CD4+ and CD8+ T lymphocytes in the tumor. We found a 14.5-fold increase in infiltration of CD8+ T cells and a 0.5-fold increase in CD8+ CD44+ memory/effector T cells in the tumors from mice treated with KRAS CV. Whereas CD4+ Foxp3+ Treg cells were decreased by 3.9-fold in the tumor. HLA-A*02 is the most common MHC class I allele. To investigate the changes in MHC expression, we conducted FACS analysis using HLA-A*02 antibodies after ex vivo treatment of KRAS CV on the human peripheral blood mononuclear cells (hPBMCs). KRAS CV treatment facilitated higher proportions of HLA-A*02+ monocytes (CD14+) and B cells (CD19+). Though LL/2 tumor model has been considered an immunosuppressive model, our results suggest that the KRAS CV can significantly enhance immune responses, thereby suppressing tumor growth. Citation Format: Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Yong Ho Heo, Seongju Jeong, Yu-Yon Kim, In Young Choi. An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB222.
Abstract LB223: Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors
Authors: Cigdem Atay Langbein, Raphael Giessel, Mahmad Ismail Housni, Kerstin Lämmermann, Barbara Bathke, André Riedl, Jürgen Hausmann, Markus Kalla, Paul Chaplin, Hubertus Hochrein, José Medina-Echeverz, Maria Hinterberger
Journal: Cancer Research (2023)

Abstract In the last decade, immunotherapy has revolutionized cancer treatment. However, the lack of potent therapy-induced immune responses against solid tumors due to the immune-suppressive tumor microenvironment (TME) is still a major drawback. One approach to reprogram TME is virotherapy, which can target tumors via destruction of infected tumor cells as well as activating immune cell populations in the TME. A versatile and safe tool for virotherapy is modified vaccinia virus Ankara (MVA), which has already been approved by the FDA as a non-replicating vaccine against smallpox and monkeypox and is also in clinical trials against other infectious diseases and cancer. In the current study, we deciphered the anti-tumorigenic effect of a novel MVA vector encoding a tumor associated antigen (TAA) and the costimulatory molecules IL-12 and 4-1BBL, called MVA-TAA-4-1BBL-IL12. We could show that repetitive intratumoral (IT) injection of MVA-TAA-4-1BBL-IL12 resulted in strong tumor growth control, shrinkage and/or complete elimination of tumors and induction of tumor-specific CD8 T cell response. Furthermore, MVA-TAA-4-1BBL-IL12 treatment promoted a systemic anti-tumor immune response not only against the treated tumor but also untreated, distant tumors. Importantly, local virotherapy also resulted in the generation of tumor-specific memory response, which protected mice against local recurrence after rechallenge. As a conclusion, our findings show that MVA-TAA-4-1BBL-IL12 IT treatment induces an effective anti-tumorigenic immune response in different solid tumor models, which gives rise to long-term protection against cancer recurrence. Citation Format: Cigdem Atay Langbein, Raphael Giessel, Mahmad Ismail Housni, Kerstin Lämmermann, Barbara Bathke, André Riedl, Jürgen Hausmann, Markus Kalla, Paul Chaplin, Hubertus Hochrein, José Medina-Echeverz, Maria Hinterberger. Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB223.
Abstract LB160: Mdm2 regulates metastasis and associated cellular processes through modulation of Sprouty4 in a p53-independent manner
Authors: Rafaela Muniz de Queiroz, Gizem Efe, Asja Guzman, Naoko Hashimoto, Yusuke Kawashima, Tomoaki Tanaka, Anil K. Rustgi, Carol Prives
Journal: Cancer Research (2023)

Abstract Mdm2 and its homologue MdmX form an E3-ligase complex that is best understood as the major regulator of p53. Yet Mdm2 and MdmX have functions in cells that are independent of their ability to degrade p53. Amongst the functions regulated by Mdm2 is cell migration, although the molecular mechanism(s) involved have not been well characterized. We show, in a p53 null model, that either siRNA knockdown of Mdm2 or MdmX as well as pharmacological inhibition of the Mdm2/X complex E3-ligase can reduce migration of cells grown as monolayer or invasion of cells from pre-formed spheroids into collagen-based matrices. This is consistent with our observation that Mdm2 ablation or inhibition leads to decreased cell spreading and attachment of cells to the extracellular matrix. In line with these findings, we found that modulation of Mdm2, MdmX or the Mdm2/X complex impacts focal adhesion (FA) formation, a main step in cell attachment, spreading and migration. Physiologically, Mdm2 silencing leads to decreased metastatic burden in mouse models. Mechanistically, we have discovered that Mdm2 modulates the RNA levels of Sprouty4 and that Sprouty4 is needed for the effects of Mdm2 knockdown on cell migration, FA formation and metastasis. Taken together, we have discovered a pathway by which Mdm2, through the activity of the Mdm2/X complex, mitigates FA formation, migration and ultimately metastasis by regulation of Sprouty4 independently of p53. Our findings suggest that blocking Mdm2 or the Mdm2/X complex might be a potential target to prevent metastasis. Citation Format: Rafaela Muniz de Queiroz, Gizem Efe, Asja Guzman, Naoko Hashimoto, Yusuke Kawashima, Tomoaki Tanaka, Anil K. Rustgi, Carol Prives. Mdm2 regulates metastasis and associated cellular processes through modulation of Sprouty4 in a p53-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB160.
Abstract LB158: Rapid cancer cell perineural invasion utilizes amoeboid migration
Authors: Qi Wang, Andrea Marcadis, Elizabeth Kao, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard Bakst, Sylvie Deborde, Richard J. Wong
Journal: Cancer Research (2023)

Abstract The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neural invasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neural-invasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associate with dorsal root ganglia than non-leading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion. Citation Format: Qi Wang, Andrea Marcadis, Elizabeth Kao, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard Bakst, Sylvie Deborde, Richard J. Wong. Rapid cancer cell perineural invasion utilizes amoeboid migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB158.
Abstract LB162: A multiplex organoid avatar drug testing platform for precision medicine
Authors: Shrey Patel, Sana Khalili, Victoria Moy, Emma Gray, Sawyer Lyons, Riley Brents, Carolyn Banister, Phillip J. Buckhaults
Journal: Cancer Research (2023)

Abstract The promise of precision medicine is to improve patient outcomes by making better therapeutic choices based on cancer causing somatic mutations. This strategy has shown limited success in colorectal cancer, in part because the genetic rules governing resistance and sensitivity are not fully elucidated. Direct drug sensitivity testing of individual patient-derived organoids is an attractive addition to this decision process because it does not require understanding of all drug-somatic mutation interactions. Individual patients avatars can be challenged with a variety of drugs and response used to inform patient care. We have developed a panel of colon cancer organoid avatars and uniquely tagged each one with a lentiviral vector possessing identifying DNA sequence bar codes flanked by common PCR primers. Each bar-code is uniquely identifiable and quantifiable from a mixture of organoids by nanopore sequencing of a common PCR product. Treatment of the mixture of organoid avatars over time under multiple drug conditions and sampling at different time points allowed the real-time monitoring of relative Darwinian fitness of each organoid in the mixture. We demonstrated the utility of this approach at identifying both expected and novel drug responses for individual organoids. Resistance to both nutlin and irinotecan were correctly predicted by TP53 somatic mutations while sensitivity to both lapatinib and ibrutinib were best predicted by mutations in EGFR signaling pathway. Patterns of drug response revealed unexpected common mechanisms. Future work will focus on informing patient care decisions with these results and determining if improvements in patient outcomes are realized. Citation Format: Shrey Patel, Sana Khalili, Victoria Moy, Emma Gray, Sawyer Lyons, Riley Brents, Carolyn Banister, Phillip J. Buckhaults. A multiplex organoid avatar drug testing platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB162.
Abstract LB085: Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer
Authors: Dewald van Dyk, Peter Zanvit, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica Pezold, John Meekin, Chien-ying Chang, Benjamin Clark, Philip L. Martin, Clare Hoover, Eric Tu, Ryan Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco
Journal: Cancer Research (2023)

Abstract Prostate cancer is traditionally considered an immunologically “cold” tumor type rendering patients insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent anti tumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumors are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a sub-optimal therapeutic index. Our target discovery and validation efforts identified STEAP2 as a superior prostate antigen for therapeutic targeting. Importantly, STEAP2 is a highly prevalent prostate cancer antigen displaying high, homogeneous cell surface expression across all stages of disease. A novel lead generation approach facilitated the development of a potent and specific armored STEAP2 CAR-T therapeutic candidate, AZD0754. This second generation CAR-T product is armored with a dominant-negative TGFβRII, thereby bolstering activity in the TGFβ-rich immunosuppressive environment of prostate cancer. Armored STEAP2 CAR-T cells demonstrate favorable in vitro properties, robust dose dependent in vivo efficacy in STEAP2 expressing cell line- and patient derived- mouse xenograft models and encouraging preclinical safety. Taken together, this data builds confidence in the specificity and potency of this potential first in class STEAP2 targeted CAR-T therapy and supports future clinical development. Citation Format: Dewald van Dyk, Peter Zanvit, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica Pezold, John Meekin, Chien-ying Chang, Benjamin Clark, Philip L. Martin, Clare Hoover, Eric Tu, Ryan Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco. Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB085.